tbuckley/cabot-search huggingface dataset:
Illuminating the Mechanisms Underlying Sex Differences in Cardiovascular Disease
Authors: Karen Reue, Carrie B. Wiese
Journal: Circulation Research (2022)

Sex is a key risk factor for many types of cardiovascular disease. It is imperative to understand the mechanisms underlying sex differences to devise optimal preventive and therapeutic approaches for all individuals. Both biological sex (determined by sex chromosomes and gonadal hormones) and gender (social and cultural behaviors associated with femininity or masculinity) influence differences between men and women in disease susceptibility and pathology. Here, we focus on the application of experimental mouse models that elucidate the influence of 2 components of biological sex-sex chromosome complement (XX or XY) and gonad type (ovaries or testes). These models have revealed that in addition to well-known effects of gonadal hormones, sex chromosome complement influences cardiovascular risk factors, such as plasma cholesterol levels and adiposity, as well as the development of atherosclerosis and pulmonary hypertension. One mechanism by which sex chromosome dosage influences cardiometabolic traits is through sex-biased expression of X chromosome genes that escape X inactivation. These include chromatin-modifying enzymes that regulate gene expression throughout the genome. The identification of factors that determine sex-biased gene expression and cardiometabolic traits will expand our mechanistic understanding of cardiovascular disease processes and provide insight into sex differences that remain throughout the lifespan as gonadal hormone levels alter with age.
OTHR-14. Responding to the COVID Challenge: evaluating a new method of adverse event recording in response to remote working.
Authors: Stephanie Reiners, Alison Barnwell, Lisa Murray, Mohamed Abdelbaki, Sally Jones, Brunilda Lluka, Heather Roemerman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The SARS-COV2 pandemic had huge impact on how clinical research is conducted when clinical research coordinators (CRC) transitioned to working remotely. An urgent transition of paper documentation into electronic formats had to occur without compromising participant safety or data integrity. Adverse event (AE) reporting had previously been captured in various paper formats with wet signature. AEs, attribution, severity, and clinical significance had to be changed into being electronically captured and incorporated into the medical record that captures the events in real time. METHOD: We assessed the satisfaction of the new method of AE recording amongst pediatric hematology oncology physicians and staff in a large academic institution during the COVID pandemic through a REDCap survey. The survey assessed the time, effort, perceived efficacy and overall acceptability of the paper-based and electronic methods of AE documentation. RESULTS: Seventy-one staff members were surveyed. Fifty (65%) responded, including 6 participants who were not involved in the AE reporting process and did not complete the survey. Of the remaining 44 participants, 43 (98%) preferred an electronic documentation method. Secondary results and further analysis will be presented at the meeting. CONCLUSIONS: The COVID pandemic has changed how CRC report AEs and electronic documentation seems to be the preferred method of documentation.
Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer
Authors: Maria Chiara De Santis, Luca Gozzelino, Jean Piero Margaria, Andrea Costamagna, Edoardo Ratto, Federico Gulluni, Enza Di Gregorio, Erica Mina, Nicla Lorito, Marina Bacci, Rossano Lattanzio, Gianluca Sala, Paola Cappello, Francesco Novelli, Elisa Giovannetti, Caterina Vicentini, Silvia Andreani, Pietro Delfino, Vincenzo Corbo, Aldo Scarpa, Paolo Ettore Porporato, Andrea Morandi, Emilio Hirsch, Miriam Martini
Journal: Gut (2022)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models.PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.
SNP-SNP interactions and a 4-locus model for prediction the risk of anthracycline-mediated cardiotoxicity in patients with breast cancer.
Authors: Dmitry Yu. Gvaldin, Natalya N. Timoshkina, Larisa N. Vashchenko, Tatiana V. Ausheva, Irina R. Dashkova, Ludmila A. Ryadinskaya, Emma E. Kechedzhieva, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2022)

12076 Background: Numerous pharmacogenetic studies have identified genetic polymorphisms (SNPs) associated with an increased risk of anthracycline-mediated cardiotoxicity (AMC). The purpose was to search for SNP-SNP interactions associated with the risk of cardiotoxic manifestations caused by anthracycline therapy in breast cancer patients. Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer with normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For SNP genotyping of c.4544G &gt; A rs8187710 (ABCC2), c.1744C &gt; T rs11549465 ( HIF1A), g.22125504G &gt; C rs1333049 ( CDKN2A/ B) and c.214T &gt; C rs4673 ( CYBA). DNA was extracted from blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic anthracycline mediated cardiotoxicity (changes developed within a year after completion of anthracycline therapy). Using the multifactorial dimension reduction method. We obtained a 4-locus model of SNP-SNP interactions c.4544G &gt; A rs8187710 ( ABCC2) x g.22125504G &gt; C rs1333049 ( CDKN2A/B) x c.214T &gt; C rs4673 ( CYBA) x g.23708527G &gt; A rs28714259 which has high prognostic properties. The specificity of the test based on the 4-locus model was 68%, the sensitivity was 100%, and the overall accuracy was 71%. The results of the analysis of SNP-SNP interactions indicate the greatest contribution of rs4673 and rs28714259 to the predisposition to AMC. The first ones yet into antagonistic interactions with rs28714259, rs1333049 and rs11549465, the second with rs8187710, rs11549465 and rs4673. On the contrary rs11549465 and rs1333049 contribute to a synergistic effect. Conclusions: The 4-locus model discovered in this study can form the basis of prognostic tests that predict early the risks of developing AMC in cancer patients, which in the future allow to personalize and select the most optimal treatment regimen.
MEDB-80. CDK8 promotes stemness of MYC-driven medulloblastoma
Authors: Dong Wang, Bethany Veo, Angela Pierce, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2022)

Abstract Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related cyclin dependent protein kinase family. CDK8 and cyclin C associate with the mediator complex to regulate gene transcription. Although CDK8 has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in medulloblastoma remains largely unknown. Here, we demonstrate how CDK8 plays an essential role in maintaining stemness and tumorigenicity in medulloblastoma stem cell. CDK8 inhibition suppresses stem cell associated signaling in medulloblastoma cells and inhibits tumor cell self-renewal. Additionally, CDK8 is amplified in MYC-driven medulloblastoma, is positively correlated with c-MYC expression in human medulloblastoma specimens and associates with poor survival in patients. Using cut&amp;run assay, we found CDK8 associates with MED1 to activate transcription of MYC target genes. CDK8 attributes to MYC-driven transcriptional programs mediating DNA repair. Pharmaceutic inhibitors and genetic depletion result in cessation of tumor growth in xenograft mouse models and increase in apoptosis and DNA damage. Collectively, our studies establish the selective inhibition of CDK8 inhibition as a viable therapeutic strategy in MYC-driven medulloblastoma.
Real-world data of lebanese patients with chronic lymphocytic leukemia.
Authors: Lewis Nasr, Intissar Yehia, Saada Diab, Ahmad Ghoche, Fadi louis Nasr
Journal: Journal of Clinical Oncology (2022)

e19512 Background: Many advances in the treatment of chronic lymphocytic leukemia (CLL) has been made in the 6 past years aiming at attaining durable complete responses and even cure. The choice of upfront therapy is driven by several factors including presence of 17p deletion or TP53 mutation, IGHV mutation status, patient fitness, comorbidities, drug availability and affordability etc.. The aim of the current study was to describe aspects of CLL in real world data setting in Lebanon regarding patients’ characteristics, diagnostic studies, indications for therapy and implication of new treatments including small molecule inhibitors including Bruton Tyrosine Kinase BTK and BCL2 inhibitors. Methods: This was an observational prospective study (2004-2021) of consecutively diagnosed patients with CLL at a single center in Lebanon. The characteristics, indication for treatment, types of treatment used were recorded progression free survival (PFS) was defined as the time from treatment initiation at first line until progression from any cause. Results: The registry covered 128 patients, 82 males and 46 females (ratio 1.78:1). Median age at diagnosis was 66 years. 23.6% were younger than 55 years. 73% of patients were asymptomatic at diagnosis, and 25% had lymphadenopathies. RAI stage 0 (BINET stage A) was observed in 73%. Median absolute lymphocytic count was 15,340 (unit), median hemoglobin was13.2. and median platelet count was 188,000. FISH panel was done in 56 patients (43%) and IGHV in 13%. 17p deletion was detected in 14.3%, and 13q deletion as a sole abnormality in 46.6%. 15.7% of patients required treatment at diagnosis; 52.6 % of them due to anemia/thrombocytopenia, and 15.8% due to presence of constitutional symptoms; other treatment indications included massive splenomegaly, and massive or symptomatic lymphadenopathy. 71 patients (55.4%) fell into the watch and wait category; 37 of which required treatment at some point during follow up with a median duration from diagnosis till starting treatment of 34 months.FCR Fludarabine + cyclophosphamide + rituximab (38.5%), BR bendamustine + Rituximab (23%), and Ibrutinib (19.2%) were the most common regimens used upfront. PFS was not reached. and correlation between genetic features and survival couldn’t be done, due to the relatively small number of patients whom showed progression. Conclusions: Epidemiologic characteristics of Lebanese patients with CLL is comparable to the international data.Molecular studies are being more implicated in the diagnostic workup. FCR and BR were mostly used upfront during the previous decade. We noticed a trend toward using Ibrutinib after 2016 in frontline and relapsed setting (after its approval and availability).
Analytical evaluation of a commercial in-house homologous recombination deficiency (HRD) assay for patients with epithelial ovarian cancers and its concordance with a reference standard.
Authors: Alberto Ranghiero, Alessandra Rappa, Davide Vacirca, Nicoletta Colombo, Elena Guerini Rocco, Massimo Barberis
Journal: Journal of Clinical Oncology (2022)

e17592 Background: Homologous recombination deficiency (HRD) is a common feature of epithelial ovarian cancers (EOCs) as approximately half of EOCs have molecular aberrations in homologous recombination repair (HRR) genes, including BRCA1/2 gene mutations. Poly ADP-ribose Polymerase inhibitors (PARPi) have reformed the management of BRCA1/2 mutant ovarian cancer patients and demonstrated activity also in tumor with HRD status. The evaluation of HRD together with BRCA1/2 gene alterations is nowadays critical to guide the therapy decision for all patients with EOC. Different methods to assessed HRD have been reported and different assays are being implemented in clinical practice. Here, we sought to evaluate the analytical validity of a commercial in house HRD assay as compared to a reference standard method. Methods: 59 consecutive case of EOCs were included in this study. DNA extracted from representative formalin-fixed paraffin-embedded (FFPE) tissue block of each case were subjected to next-generation sequencing (NGS) analysis of BRCA1/2 genes alterations and HRD status using the AmoyDx HRD Focus Panel (Amoy Diagnostics Ltd, Xiamen, Fujian, China). HRD status was assesses through AmoyDx Genomic Scar Score (GSS) considering the length, type and location of the genome-wide chromosomal copy number variation through SNP probes spread throughout the genome. Cases with a GSS &gt; 50 were considered as HRD positive. For each case the same FFPE tissue block was sent to Myriad Genetic Laboratories for myChoice CDx testing as reference standard. Assay concordance was measured as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement according to the different scores proposed by the manufacturers. Results: HRD status data were available for 52 (88.1%) and 56 (94.9%) samples considering in-house and reference standard assay, respectively, and 49 cases was available for concordance analyses. AmoyDx HRD Focus Panel identified 23/49 samples (46.9%) as HRD positive and 26 (53.1%) as HRD negative. The concordance of HRD status between AmoyDx HRD Focus Panel and myChoice CDx was 100% and 81,2% for positive (PPA) and negative (NPA) cases respectively, with an overall analytical concordance (OPA) of 87.8%. No discordance was seen in BRCA1/2 status between in-house and reference standard assay (OPA: 100%). Conclusions: The HRD status assessed by AmoyDx HRD Focus Panel is highly concordant with that obtained using the current standard reference method. Commercial in-house test may offer a cost-effective, reliable and robust alternative to the centralized assay for the evaluation of HRD status in patient with EOC.
ATRT-21. Contribution of germline mosaic alterations of SMARCB1 in rhabdoid tumor predisposition syndrome
Authors: Julien Masliah-Planchon, Laetitia Maillot, Noémie Rybak, Fatoumata Simaga, Abderaouf Hamza, Marion Gauthier Villars, Olivier Delattre, Franck Bourdeaut
Journal: Neuro-Oncology (2022)

Abstract Rhabdoid tumors are rare and aggressive tumors that usually arise in very young children. They are characterized by a bi-allelic inactivation of the SMARCB1 gene. Although the majority of alterations of SMARCB1 are acquired in tumors, a heterozygous germline alteration is seen in one third of patients and defines the rhabdoid tumors predisposition syndrome. Penetrance is almost complete and the vast majority of germline alterations of SMARCB1 are acquired de novo but rare familial cases with a healthy carrier have also been described. Since the advent of more sensitive molecular analysis technologies such as next-generation sequencing (NGS), the number of mosaicisms of genes involved in genetic diseases discovered from blood samples has increased considerably. The aim of our study was to explore the mosaicisms of SMARCB1 in the blood 1/ of children with rhabdoid tumors with at least one alteration of SMARCB1 previously identified in the tumor but not found in the blood with old-fashioned low-sensitivity technologies and 2/ in parents of children with heterozygous germline alteration of SMARCB1. We analyzed a custom NGS panel which covers the SMARCB1 gene with an average depth of 1.500X on blood samples of 111 children with rhabdoid tumors and 32 parents collected at the Institut Curie since 1999. The mosaicism rate found in index cases was 11.7% (13/111) and 3.1% (1/32) in parents. The variant allele frequency vary from 0.8% to 12.9%. Our results also indicate to be cautious about the possible confounding effect of circulating tumor DNA. This hitherto underestimated SMARCB1 mosaicism rate should motivate an optimization of the genetic counseling as well as the oncological monitoring of these children and thus have a significant medical impact given the catastrophic prognosis of rhabdoid tumors.
Immune-related adverse effects of long-term PD-1/PD-L1 inhibtor treatment.
Authors: Sarah Kim, A. Dimitrios Colevas, Stephanie Tse, Sandy On, Edna Cheung
Journal: Journal of Clinical Oncology (2022)

2661 Background: Immune-related adverse effects (irAE) are autoimmune-like toxicities caused by immune checkpoint inhibitor (ICI) treatment and often necessitate interventions such as corticosteroids, treatment interruptions/discontinuation, or hospital admission. Although ICI related irAEs are well described in literature, data on the toxicity profile associated with long-term ICI use remains limited. Since the optimal duration of therapy with ICI agents is currently unknown, it is crucial to assess the risks of long-term ICI use. Methods: This was a retrospective, observational, single-center study of adult oncology patients who received at least 1 year of programed death 1 (PD-1) inhibitor or programmed death ligand-1 (PD-L1) inhibitor treatment. The objective of this study was to characterize late-onset irAEs defined as greater than 1 year with long-term ICI treatment. Clinically significant irAEs were defined as those requiring corticosteroid treatment, hospital admission, treatment interruption or treatment discontinuation. This study included patients who received at least 1 year of nivolumab, pembrolizumab, atezolizumab or durvalumab between January 2016 and September 2021. Disease states included head and neck cancer, renal cell carcinoma, non-small cell lung cancer, and melanoma. Patients with concurrent exposure to other treatment such as chemotherapy, radiation, surgery, tyrosine kinase inhibitors and monoclonal antibodies while on ICI treatment were included in the study. Exclusion criteria included patients with treatment breaks of greater than 6 months, two malignancies undergoing active treatment, and treatment administration outside of the study center. Results: Of 282 patients assessed, 143 met study inclusion criteria. The median ICI treatment duration was 19 months (IQR 14-27). There was a 30% incidence of late-onset irAEs, of which 22% were clinically significant. Most late-onset irAEs were low in severity, as 45 (90%) were grade 1-2 and 5 (10%) were grade 3. The most common late-onset irAEs were pulmonary (8%) and gastrointestinal (7%). Univariate analysis suggests risk factors potentially associated with late-onset irAEs include concurrent exposure to additional therapies during ICI treatment and past medical history of rheumatologic disease. Conclusions: Although the optimal duration of ICI therapy is unknown, this study suggests that long-term ICI use was associated with a low but notable incidence of toxicities, of which most were low in severity. [Table: see text]
Facilitating Equitable, High-Quality Cancer Screening in the Post–COVID-19 Era
Authors: Jennifer C. Spencer, Michael P. Pignone
Journal: JAMA Network Open (2022)

Stacey A. Fedewa, PhD; Jessica Star, MA, MPH; Priti Bandi, PhD; Adair Minihan, MPH; Xuesong Han, PhD; K. Robin Yabroff, MBA, PhD; Ahmedin Jemal, DVM, PhD
GCT-12. SIOP CNS GCT II: High Risk (HR) CNS Non-germinomatous Germ Cell Tumours (NGGCT) treated with Dose intensified PEI – final results
Authors: Gabriele Calaminus, Didier Frappaz, Thankamma Ajithkumar, Jans-Enno Müller, Martin Zimmermann, Cecile Faure Conter, Beate Timmermann, Claire Alapetite, Matthew Murray, Maria Luisa Garre, Karin Dieckmann, Andreas Peyrl, Nicolas U Gerber, Rolf-Dieter Kortmann, James Nicholson
Journal: Neuro-Oncology (2022)

Abstract Based on results of SIOP CNS GCT 96, patients enrolled in SIOP CNS GCT II with AFP higher or 1000 ng/ml (serum and/or CSF) and/or age less than 6 years with NGGCTs at diagnosis received two standard cycles of PEI and two higher dose PEI courses followed by radiotherapy according to dissemination (54 Gy local RT or 30 Gy CSI/24 Gy tumour boost). Between 2/2012 and 7/2018, 112 patients with CNS NGGCT were registered, of whom 23 were identified as HR patients; 18/23 had an AFP higher or 1000 ng/ml and were older than 6 years. Five children were &amp;lt; 6 years and showed YST elements in histology. of whom 3 received chemotherapy alone due to age. Primary site was pineal in 15/23, suprasellar in 5/23, bifocal in 3/23 patients; 3/23 patients were metastatic at diagnosis and 9/23 patients relapsed. Three years EFS was 0.60±0.10 with a median observation time of 3.96 years. Two recurrences were local, 4 distant (metastatic) and 3 combined, local and distant. HR CNS NGGCTs appeared to benefit from dose intensified PEI, compared with those treated in SIOP CNS GCT 96 with standard dose PEI. These results support the further exploration of this chemotherapy regimen in future clinical trials in such patient groups, including the consideration of delivering three dose intensified courses after one standard chemotherapy course, as is the practice in some groups treating very high risk extracranial GCTs.